Recently, great progress has been achieved in the understanding of the morphogenic aspects of hair follicle (HF) biology, nevertheless, the molecular and genetic aspects of hair growth control remain largely unknown. Among these, the molecular pathways of HF catagen transformation are the least well understood despite the abnormalities of catagen progression underlie many common hair disorders in humans. Recent studies showed that catagen is an apoptosis-driven process and programmed cell death is the major mechanism of catagen HF transformation. Our previous studies indicated that ectopic and premature apoptosis in HF matrix is the major defect in the mutant hr/hr hairless mouse skin that causes the complete hair loss. These findings implicate the hairless (hr) gene as a key factor in coordinating basic cellular processes during HF catagen and programmed cell death as a possible key target of hr gene activity. In order to gain the further insights into the molecular control of HF functions by hr, we propose the use of the native skin and cultured keratinocytes derived from the mutant (hrrh/hrrh) hairless mice as a model for elucidation the role of hr gene in regulation of apoptosis-driven catagen and for the identification of the downstream targets of hr gene activity. The hypothesized involvement of hr gene into apoptotic regulatory pathway will be tested using morphological methods, TUNEL and annexin V staining along with functional experiments (comparison of apoptosis-associated gene expression in hr/hr and wt skin under UVB irradiation, treatment with DFMO and ICE and caspase-3 inhibitors). Using Northern Blot analysis and immunohistochemistry, we will test the expression patterns of presumptive downstream targets of the hr-dependent regulatory pathway in wt and hr/hr skin. The search for unknown targets of hr gene activity will be performed using hybridization arrays with nucleic acids isolated from intact mouse epidermis of both hrrh/hrrh and wt genotypes. Identified candidate target genes will be prioritized according to their known role in hair follicle physiology, and also according to data obtained from our functional experiments and immunohistochemical studies. Thus, the experiments outlined in this proposal are designed to dissect the cellular and molecular mechanisms of hair follicle catagen transformation using the hairless phenotype as an experimental model. Elucidation the role of hr gene in apoptosis regulation and discovery of the genes directly implicated in a hr-dependent pathway would have far-reaching implications for the understanding of basic mechanisms of hair growth control and potentially, for the development of novel drugs that target the control of catagen as the most relevant clinical problem of hair biology.